Predictors of recurrence based on intravascular ultrasound findings after Eluvia placement in symptomatic peripheral arterial disease: A retrospective study

Abstract Background and Aims Polymer‐coated drug‐eluting stents (Eluvia) have shown favorable clinical outcomes in real‐world registries. There are no reports on recurrent predictors after Eluvia placement based on intravascular ultrasound (IVUS) findings. Methods We analyzed clinical data from the ASIGARU PAD registry, a retrospective, multicenter, observational study that enrolled patients who underwent endovascular therapy for superficial femoral and proximal popliteal arteries lesions using Eluvia or drug‐coated balloon. The primary outcome was the identification of recurrent predictors, including IVUS parameters at 12 months. The rate of target lesion recurrence was also assessed. Results IVUS images were obtained in 54 of 65 cases. Seven recurrent cases (13.0%) were observed within 12 months. The random survival forest method presented eight predictive variables of recurrence: Clinical Frailty Scale (CFS), distal stent edge area, distal plaque burden, age, sex, distal external elastic membrane (EEM) area, minimum stent area (MSA), and distal lumen area. Furthermore, the partial dependence plot showed that frailty (CFS ≥ 6), smaller distal stent edge area, higher and lower distal plaque burden, older and younger age, female sex, smaller distal EEM area, smaller MSA, and smaller and larger distal lumen area predicted recurrence after Eluvia placement within 12 months. Conclusion CFS, distal stent edge area, distal plaque burden, age, sex, distal EEM area, MSA, and distal lumen area were significant recurrent predictors after Eluvia placement.


| INTRODUCTION
The 2017 European Society of Cardiology guidelines indicate that plain old balloon angioplasty (POBA) and bare-metal stent (BMS) implantation are the current standard endovascular revascularization strategies for femoropopliteal lesions. 1 However, the recurrence rates after POBA and BMS placement were reported to be 43%-68% and 24%-36% at 1 year, respectively, and this high rate is an important issue. [2][3][4][5][6] Although a polymer-free drug-eluting stent (DES), launched in 2012, presented a good primary patency rate of 83.1% at 1 year and 66.4% at 5 years in a pilot randomized controlled trial, 6,7 the ZEPHYR registry revealed insufficient primary patency of 50% at 1 year in patients with severe lesion characteristics. 8 There have been significant recent advances in drug technology. The polymer-coated DES (Eluvia, Boston Scientific) showed significantly improved primary patency compared with polymer-free DES. 9 Eluvia also yielded favorable patency rates in real-world registries with severe lesion characteristics, confirming its usefulness in a clinical setting. [10][11][12] Although several predictors of recurrence after Eluvia placement have been mentioned in real-world registries, the evidence is still limited. 10,12 Moreover, there are no reports on predictors of recurrence after Eluvia placement based on intravascular ultrasound (IVUS) findings.

| Participants
We screened clinical data from the ASIGARU PAD registry, which included consecutive patients with lower extremity artery disease (LEAD) who underwent endovascular therapy (EVT) for femoropopliteal artery lesion between January 2018 and December 2019. The registry is an ongoing, retrospective, multicenter, observational registry of LEAD, and current data include information from five institutions in the Tokai area in Japan. The inclusion and exclusion criteria details were described previously. 12 A total of 151 consecutive patients and 151 cases were enrolled, and divided into two groups as follows: 65 cases in the Eluvia group and 86 cases in the drug-coated balloon group. Of the 65 cases in the Eluvia group, patients for whom IVUS images were obtained were evaluated in this study ( Figure 1).

| Endovascular revascularization and follow-up protocol
On the basis of the current guidelines and the package insert instructions of the Eluvia, 1 dual antiplatelet therapy (DAPT) was primarily employed for at least 2 months. In some cases, type and dosage of antithrombotic agents were adjusted according to the physician's discretion. After sheath insertion, intra-arterial or intravenous heparin bolus was administered as anticoagulation during the procedure in all cases. The heparin dose was left to the investigators' discretion, and activated clotting time was controlled between 250 and 300 s. Eluvia was implanted, covering the entire lesion, and placed in the least plaque burden area possible.
Clinical follow-up was conducted at baseline, 1, 3, 6, and 12 months. In addition, examination of ankle-brachial index (ABI) pressure was performed at each visit, and duplex ultrasound (DUS) was performed at 6 and 12 months.

| IVUS analysis
At least two experienced physicians reviewed the IVUS data at each institution. Lesion evaluation using IVUS was performed after wire passage and at the end of the procedure. IVUS data were analyzed using serial images containing proximal and distal information of the lesion. The evaluated IVUS parameters were proximal and distal external elastic membrane (EEM) area, lumen area, stent lumen area, landing plaque burden, and stent edge dissection. In addition, the calcification angle, stent lumen eccentricity, and minimum stent area (MSA) of the entire lesion were also assessed. For chronic total occlusion (CTO) lesions, the wire passage route was also investigated.

| Study outcomes
The primary outcome was the identification of predictors of recurrence after Eluvia placement, including IVUS parameters at 12 months. The secondary outcome was target lesion recurrence at 12 months.

| Definitions
Hypertension was defined as systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg according to the 2017 American College of Cardiology/American Heart Association guidelines for hypertension and/or a history of treatment with antihypertensive medication.
Dyslipidemia was defined as low-density lipoprotein cholesterol ≥140 mg/dL, high-density lipoprotein cholesterol <40 mg/dL, or triglyceride ≥150 mg/dL, and/or a history of treatment with antidyslipidemic medication. Diabetes mellitus was defined based on medical history, plasma glucose level, or glycosylated hemoglobin level. The severity of frailty was categorized into three groups as 1-3 (well activities), 4-5 (mild frailty), and 6-8 (moderate or severe frailty) based on the Clinical Frailty Scale (CFS). 13 The clinical severity of LEAD was assessed using the Rutherford classification, which consists of seven grades (0-6). The femoropopliteal lesion severity was assessed using the Trans-Atlantic Inter-Society Consensus (TASC II) classification. The angiographic lesion calcification was evaluated using the peripheral artery calcification scoring system (PACSS) consisting of five grades (0-4), and PACSS grade 4 was defined as severe calcification. 14 The EEM was defined as the area bounded by the leading adventitial edge, and the lumen area was defined as the area bounded by the luminal border. 15 The stent edge area was measured as the area inside the stent within 2 mm of the stent edge. The MSA was defined as the smallest area bounded by the stent border. 15 The plaque burden was calculated by dividing the lumen area by the EEM at the stent edge. 16 The stent edge dissection was evaluated using the coronary artery dissection classification. 17 The stent lumen eccentricity was calculated using the following formula: Minimum stent diameter)/maximum stent diameter. 15 The wire passage route was classified based on the IVUS findings: intraplaque, inside the plaque; subintimal, between the plaque and media; and intramedial, between the media and adventitia. 18 Technical success was defined as successful completion of the procedure with ≤30% residual stenosis. The target lesion recurrence was defined as a peak systolic velocity ratio ≥2.5 by DUS, >50% stenosis by angiography, or an ABI decrease >0.15 or revascularization. Recurrence patterns were categorized into three grades: Tosaka I (focal stenosis), Tosaka II (diffuse stenosis), and Tosaka III (occlusion). 19

| Statistical analysis
Continuous data are presented as mean ± standard deviation.
Categorical data are presented as counts (percentages). An unpaired t test was used to compare continuous variables, and the χ 2 test was used for categorical data. Recurrence predictors were detected using the random survival forest (RSF) method, which is an extension of Breiman's random forest method, allowing efficient nonparametric analysis of time-to-event data. 20,21 According to the RSF, variables with variable importance (VIMP) of >0.002 were defined as potentially predictive, and variables with larger VIMP were considered more predictive. 20 Moreover, the relationship between the variables and primary patency, and the cutoff points of each predictor were assessed using the partial dependence plot (PDP) method. 22 The PDP can show whether the relationship between the variables and a feature is linear, monotonic, or more complex. We used the

| Baseline clinical characteristics
Of the 65 cases, IVUS images were obtained from 54 cases. The baseline clinical characteristics are shown in Table 1

| Lesion and procedural characteristics
The lesion and procedural characteristics are presented in Table 2.
The mean total lesion length was 182.5 mm, and 66.7% had CTO.
Severe calcification was observed in 20.4% of the cases. All Eluvia were successfully implanted, covering the entire target lesion, and technical success was achieved in all cases. Pre-and postdilatation YAMADA ET AL.
were performed in 98.1% of cases, and the mean total stent length was 207 mm.

| IVUS findings
The IVUS findings are presented in Table 3. The mean EEM area was 47.9 mm 2 in the proximal portion and 34.5 mm 2 in the distal portion.
Calcification occupying more than 270 degrees of the lumen was observed in 29.6% of cases. At the end of treatment, the mean plaque burden was 40.8% in the proximal stent edge, 40.2% in the distal stent edge, and the mean MSA was 16.8 mm 2 . Stent edge dissection was observed in 25.5% of cases, and dissection extending behind the plaque was observed in 5.9%.

| Recurrence rate and predictors of recurrence
The clinical results are presented in Table 4. Of the 54 cases, 7 (13.0%) cases of recurrence were observed within 12 months.
Two cases had focal stenosis (Tosaka I), four cases had total occlusion (Tosaka III), and one case was unknown because an angiographic examination was not performed. The characteristics of each recurrence case are summarized in the case series ( Table 5). The RSF presented eight predictive variables of recurrence ( Figure 2): CFS, distal stent edge area, distal plaque burden, age, sex, distal EEM area, MSA, and distal lumen area.
Furthermore, PDP showed that frailty (CFS ≥ 6), smaller distal stent edge area, higher and lower distal plaque burden, older and younger age, female sex, smaller distal EEM area, smaller MSA, and smaller and larger distal lumen area predicted recurrence after Eluvia placement within 12 months (Figure 3). In contrast, diabetes mellitus, dialysis-dependent status, CLTI, CTO, the severity of calcification, lesion length, and stent edge dissection were not significant predictors of recurrence after Eluvia placement. In this study, eight predictors of recurrence after Eluvia placement were identified. Of these, three were patient characteristics, and five were IVUS findings. A unique aspect of this study was that the IVUS parameters correlated more strongly with recurrence than did lesion characteristics that could be identified by angiography, such as lesion length, CTO, and PACSS grade. This result is supported by the fact that the Munster all-comer registry did not identify angiographic lesion characteristics as a recurrence factor. 23 Next, we considered individual factors. Female sex has been reported to be a recurrent factor in previous devices, and the results of our study were similar. 26,27 Frailty is most often defined as an aging-related syndrome of physiological decline, characterized by marked vulnerability to adverse health outcomes. The progression of frailty has been reported to affect the outcomes of various diseases. 28,29 It has been suggested that one of the pathological conditions of frailty is a decrease in the "physiological reserve", and poor microvasculature of lower extremity and disorder of angiogenesis due to muscle reduction maybe the essence of the cause of the increased recurrence rates. 30 previous study reported that the recurrence rate of the femoropopliteal lesions after EVT was higher in frail patients than in nonfrail patients, and the results of this study were also similar. 32 Concerning age, a strong correlation was found with increasing age and a weak correlation with decreasing age. We hypothesized that elderly patients generally tend to have poor backgrounds, such as various diseases and frailty, leading to higher a recurrence rate. Younger patients with LEAD also tend to have several risk factors. The status of antithrombotic therapy is an important factor in considering patency loss after treatment with Eluvia placement. A previous study has reported that DAPT was able to decrease the TLR rate at 6 months; however, the efficacy did not last up to 12 months. 33 In our study, DAPT was not a significant predictor for recurrence of superficial femoral and proximal popliteal arteries lesions, and the result was consistent with the previous report. These recurrence predictors of the patient characteristics were consistent with our main report. 12 Patients with recurrence predictors such as female, severe frailty, and elderly and younger age may be better treated by appropriate devices other than Eluvia. Distal EEM area, distal lumen area, distal stent edge area, distal plaque burden, and MSA were identified as predictors of recurrence related to the IVUS findings. Although the distal lumen area and distal plaque burden showed bilateral correlation (smaller and larger, lower and higher, respectively), most cases with larger distal lumen area or lower distal plaque burden corresponded to multiple patient characteristics predictors as shown in the case series (Table 5). Small distal vessel factors were consistently related to recurrence predictors.
Our study revealed that small vessels and high plaque burden were predictors of recurrence in polymer-coated DES, as well as in BMS and polymer-free DES. 8,16 Small vessels tend to lead to small MSA, and a high plaque burden tends to lead to a small stent edge area. Therefore, acquiring a substantial stent lumen area may be a challenge for Eluvia placement.
The following conclusions can be drawn from our study results: to maintain patency of Eluvia in daily clinical practice, it is important to (1) assess vascular information using IVUS, (2)  full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

ACKNOWLEDGMENTS
The authors especially thank the catheterization laboratory medical staff and other ASIGARU investigators at each institution for their assistance. We also acknowledge Taro Shibahara, Masaru Nagase, Daiju Ono, Gen Tanabe, Keita Suzuki, Makoto Yamaura, Takahisa Ido, Takashi Nakashima, and Shigekiyo Takahashi for their technical support.

CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
The data sets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

ETHICS STATEMENT
This study was conducted following the Declaration of Helsinki and was approved by the ethical committee of each institution (ID: 2020-036). Written informed consent was obtained from each patient or their relative before the index procedure.

TRANSPARENCY STATEMENT
The lead author Takehiro Yamada affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.